Accumulating evidence strongly associates human papillomavirus (HPV) infection with the development of cervical precancers and cancer. The specific role of HPV in cervical neoplasia has not been established d few studies to date have examined the natural history of HPV from latent infection to neoplasia. Studies documenting the presence of HPV DNA in disease free women suggest that co-factors are required by HPV for neoplasia to occur. The purpose of this study is 1) to continue a longitudinal natural history of human papillomavirus (HPV) from early infection to high grade (HG) squamous intraepithelial lesion (SIL) in young women who have had a history of a positive test for HPV DNA and to continue the examination of cofactors (Chlamydia trachomatis, herpes simplex virus, oral contraceptive use, cigarette use and biologic cervical immaturity) associated with the development of low grade (LG) SIL and HGSIL, 2) to examine within this cohort events, specifically viral persistence or transition from low to high level persistence, that may precede and predict the development of significant cervical disease and to examine factors that influence these events. In addition, the study will examine co-factors associated with the regression of LGSIL and associated with HPV conversion from negative to positive in our cohort. Methods: 985 women (794 HPV positive and 191 HPV negative aged 13-22 years will have been recruited into a case-control study. Women who participate are asked to undergo a colposcopic examination and face-to-face interview. Women with no evidence of HGSIL are enrolled in the longitudinal study. We estimate that 799 women will be currently active in the prospective cohort by June, 1994. Patients will be examined every 4 months (controls are seen every 6 months) or until HGSIL develops. Colposcopic examinations, cytology, test for C. trachomatis, herpes simplex virus, nicotine/cotinine levels of cervical mucous and face-to-face interviews for information on sexual behaviors, contraceptive use, and cigarette use will be performed at scheduled intervals. Data analysis will emphasize the identification of cofactors associated with LGSIL and HGSIL development with emphasis on the role of persistence, transition from low to high level persistent infection, and regression of LGSIL. The results from this study will be related to the prevention and education of pre-cancer lesions in young women as well as identifying a clinical model for the role of viruses in abnormal cellular development.